1. Field of the Invention
This invention relates to the preparation of taxol and 10-deacetyltaxol by partial synthesis starting from various naturally occurring taxane-7-xylosides.
2. Related Art
Taxol was first isolated in 1971 from the western yew, Taxus brevifolia by Wani et al. ([1971] J. Am. Chem. Soc. 93:2325), who characterized its structure by chemical and X-ray crystallographic methods.
Taxol is a member of the taxane family of diterpenes having the following structure: ##STR1## Taxol and various taxane derivatives, including cephalomannine and taxol C, are highly cytotoxic and possess strong in vivo activity in a number of leukemic and tumor systems. In recent studies, taxol has become an exceptionally promising cancer chemotherapeutic agent, and has been approved for use by the Food and Drug Administration (FDA). However, the major problem encountered during the clinical trials conducted for FDA approval was the limited availability of the compound. That problem remains. Various techniques for increasing the supply of taxol are the subject of active research. Strategies being studied include total synthesis, partial synthesis (from readily available taxol precursors), extraction from Taxus needles, cultivation of Taxus plants, identification of simpler drug analog, and cell culture production.
Because of the structural complexity of taxol, partial synthesis is a far more viable approach to providing adequate supplies of taxol than total synthesis. The first successful partial synthesis of taxol was developed by J. N. Denis et al. ([1988] J. Am. Chem. Soc. 110:5917; U.S. Pat. No. 4,924,011). The starting material for the partial synthesis, 10-deacetylbaccatin III, can be extracted in relatively high yield from the leaves of Taxus baccata. However, thus far, no other naturally occurring taxol precursors have been employed in the partial synthesis of taxol.
Senilh et al. ([1984] J. Nat. Prod. 47:131) isolated a number of taxane xylosides from the bark of Taxus baccata. The major xyloside isolated in that study was 10-deacetyltaxol-7-xyloside (0.022%). 10-deacetyltaxol-7-xyloside was also isolated from the bark of T. brevifolia, together with taxol-7-xyloside, 10-deacetylcephalomannine-7-xyloside, and 10-deacetyltaxol C-7-xyloside. Among these various compounds, 10-deacetyltaxol-7-xyloside appears to be one of the major components of the bark. Some batches of bark yield 0.1% or more of this compound which is nearly 5 times as much as that reported earlier by Senilh. Thus, it would be desirable to use 10-deacetyltaxol-7-xyloside as a starting material to synthesize taxol. Unfortunately, all previous attempts at converting 10-deacetyltaxol-7-xyloside into taxol have failed. The present invention addresses this need by providing a process for the conversion of 10-deacetyltaxol-7-xyloside and other taxol precursors to taxol.